Anti-inflammatory 17.β.-carbothioate ester derivatives of androstane with a cyclic ester group in position 17.α

ABSTRACT

There are provided compounds of formula (I) 
                         
wherein the variables are as defined by the present specification; and solvates thereof, processes for preparing them and their use in therapy.

This application is filed pursuant to 35 USC 371 as a United StatesNational Phase Application of International Patent Application SerialNo. PCT/GB02/01971 filed 30 Apr. 2002, which claims priority from: GB0110578.2 filed on 30 Apr. 2001; GB 0127988.4 filed on 22 Nov. 2001; GB0202442.0 filed 2 Feb. 2002; and GB 0202637.5 filed on 5 Feb. 2002, allof which were filed in the United Kingdom.

The present invention relates to novel anti-inflammatory andanti-allergic compounds of the androstane series and to processes fortheir preparation. The present invention also relates to pharmaceuticalformulations containing the compounds and to therapeutic uses thereof,particularly for the treatment of inflammatory and allergic conditions.

Glucocorticoids which have anti-inflammatory properties are known andare widely used for the treatment of inflammatory disorders or diseasessuch as asthma and rhinitis. For example, U.S. Pat. No. 4,335,121discloses6α,9α-Difluoro-17α-(1-oxopropoxy)-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester (known by the generic name of fluticasonepropionate) and derivatives thereof. The use of glucocorticoidsgenerally, and especially in children, has been limited in some quartersby concerns over potential side effects. The side effects that arefeared with glucocorticoids include suppression of theHypothalamic-Pituitary-Adrenal (HPA) axis, effects on bone growth inchildren and on bone density in the elderly, ocular complications(cataract formation and glaucoma) and skin atrophy. Certainglucocorticoid compounds also have complex paths of metabolism whereinthe production of active metabolites may make the pharmacodynamics andpharmacokinetics of such compounds difficult to understand. Whilst themodern steroids are very much safer than those originally introduced itremains an object of research to produce new molecules which haveexcellent anti-inflammatory properties, with predictable pharmacokineticand pharmacodynamic properties, with an attractive side effect profile,and with a convenient treatment regime.

Certain novel androstane derivatives are disclosed in WO02/12265 andWO02/12266 (Glaxo Group), both of these documents being published afterthe earliest priority date of this patent application.

We have identified a novel series of glucocorticoids, whichsubstantially meets these objectives.

Thus, according to one aspect of the invention, there is provided acompound of formula (I)

wherein

-   R₁ represents C₁₋₆ alkyl or C₁₋₆ haloalkyl;-   R₂ represents C₃₋₈ cycloalkyl or C₃₋₈ cycloalkenyl either of which    may optionally be substituted by one or more groups selected from    oxo, methyl, methylene and halogen;-   R₃ represents hydrogen, methyl (which may be in either the α or β    configuration) or methylene;-   R₄ and R₅ are the same or different and each represents hydrogen or    halogen; and    represents a single or a double bond;    and solvates thereof.

Examples of solvates include hydrates.

References hereinafter to a compound according to the invention includesboth compounds of formula (I) and solvates thereof.

It will be appreciated that the invention includes within its scope allstereoisomers (including enantiomers and diastereoisomers) of thecompounds of formula (I) and mixtures thereof.

Preferably, the absolute stereochemistry will be as shown in therepresentation of compounds of formula (I).

Examples of C₁₋₆ haloalkyl that R₁ may represent include C₁₋₆ alkylsubstituted by 1–3 halogen atoms, preferably 1 halogen atom. Preferredhalogen atoms are selected from bromine, chlorine and fluorine.

Examples of C₃₋₆ cycloalkyl groups that R₂ may represent includecyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl and substitutedderivatives such as methylcyclopropyl (eg 1-methylcyclopropyl or2-methylcyclopropyl), dichlorocyclopropyl (eg 2,2-dichloropropyl),methyldichlorocyclopropyl (eg 1-methyl-2,2-dichlorocyclopropyl),exomethylenecyclobutyl (eg 3-exomethylenecyclobutyl),tetramethylcyclopropyl (eg 2,2,3,3-tetramethylcyclopropyl) andmethycyclobutyl (eg 1-methylcyclobutyl). Other examples includedimethylcyclobutyl (eg 3,3-dimethylcyclobutyl), difluorocyclobutyl (eg3,3-difluorocyclobutyl), methylcyclopentyl (eg 1-methylcyclopentyl). Afurther example includes oxocyclobutyl (eg 3-oxocyclobutyl).

Examples of C₃₋₄ cycloalkenyl groups that R₂ may represent includealkenyl groups containing 1 or more double bonds (not being aromaticgroups) such as cyclohexenyl eg cyclohex-2,3-enyl.

We prefer R₁ to represent fluoromethyl, chloromethyl, bromomethyl or2′-fluoroethyl, especially fluoromethyl.

Preferably, R₂ represents C₃₋₈ cycloalkyl or C₃₋₈ cycloalkenyl either ofwhich may optionally be substituted by one or more groups selected frommethyl, methylene and halogen. In an alternative aspect, R₂ representsC₃₋₈ cycloalkyl or C₃₋₈ cycloalkenyl either of which may be substitutedby oxo eg 3-oxocyclobutyl.

We prefer R₂ to represent C₃₋₈ cycloalkyl optionally substituted by oneor more methyl and/or halogen groups. We particularly prefer R₂ torepresent C₃₋₆ cycloalkyl, more preferably C₃₋₄ cycloalkyl, optionallysubstituted by one or more methyl or chlorine groups.

We also prefer R₂ to represent C₃₋₆ cycloalkyl substituted by methylene.

In one set of preferred compounds, R₂ is unsubstituted or substituted byat most one methyl or chlorine group. More preferably, R₂ is substitutedby one methyl group, especially in the 1-position, eg 1-methylcyclopropyl or 1-methyl-cyclobutyl.

In another set of preferred compounds, R₂ is substituted by more thanone methyl group, eg 2,2,3,3-tetramethylcyclopropyl.

We prefer R₃ to represent methyl, especially methyl in the αconfiguration.

Compounds of formula (I) in which R₄ and R₅, which can be the same ordifferent, each represents hydrogen, fluorine or chlorine, particularlyhydrogen or fluorine, are preferred. Especially preferred are compoundsin which both R₄ and R₅ are fluorine.

Preferably,

represents a double bond.

It is to be understood that the present invention covers allcombinations of particularly and preferred groups referred tohereinabove.

Preferred compounds of formula (I) include:

-   17α-(Cyclobutylcarbonyl)oxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic    acid S-fluoromethyl ester;-   17α-(Cyclopentylcarbonyl)oxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic    acid S-fluoromethyl ester;-   17α-(Cyclohexylcarbonyl)oxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic    acid S-fluoromethyl ester;-   17α-(Cyclopropylcarbonyl)oxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic    acid S-fluoromethyl ester;-   6α,9α-Difluoro-11β-hydroxy-16α-methyl-17α-(3-methycyclopropylcarbonyl)oxy-3-oxo-androsta-1,4-diene-17β-carbothioic    acid S-fluoromethyl ester;-   6α,9α-Difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(2,2,3,3-tetramethycyclopropylcarbonyl)oxy-androsta-1,4-diene-17β-carbothioic    acid S-fluoromethyl ester;-   17α-(2,2-Dichloro-1-methycyclopropylcarbonyl)oxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic    acid S-fluoromethyl ester;-   17α-(2,2-Dichlorocylopropylcarbonyl)oxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic    acid S-fluoromethyl ester;-   6α,9α-Difluoro-11β-hydroxy-16α-methyl-17α-(3-methylenecyclobutylcarbonyl)oxy-3-oxo-androsta-1,4-diene-17β-carbothioic    acid S-fluoromethyl ester;-   6α,9-Difluoro-11β-hydroxy-16α-methyl-17α-(2-methylcyclopropylcarbonyl)oxy-3-oxo-androsta-1,4-diene-17β-carbothioic    acid S-fluoromethyl ester;-   6α,9α-Difluoro-11β-hydroxy-16α-methyl-17α-(1-methylcyclobutylcarbonyl)oxy-3-oxo-androsta-1,4-diene-17β-carbothioic    acid S-fluoromethyl ester;-   6α,9α-Difluoro-17α-(3,3-dimethylcyclobutylcarbonyl)oxy-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic    acid S-fluoromethyl ester;-   6α,9α-Difluoro-17α-(3,3-difluorocyclobutylcarbonyl)oxy-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic    acid S-fluoromethyl ester;-   6α,9α-Difluoro-11β-hydroxy-16α-methyl-17α-(1-methylcyclopentylcarbonyl)oxy-3-oxo-androsta-1,4-diene-17β-carbothioic    acid S-fluoromethyl ester;-   6α,9α-Difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(3-oxocyclobutylcarbonyl)oxy-androsta-1,4-diene-17β-carbothioic    acid S-fluoromethyl ester.

One particularly preferred compound is the following:

-   6α,9α-Difluoro-11β-hydroxy-16α-methyl-17α-(1-methycyclopropylcarbonyl)oxy-3-oxo-androsta-1,4-diene-17β-carbothioic    acid S-fluoromethyl ester.

Another particularly preferred compound is the following:

-   6α,9α-Difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(2,2,3,3-tetramethycyclopropylcarbonyl)oxy-androsta-1,4-diene-17β-carbothioic    acid S-fluoromethyl ester.

Another particularly preferred compound is the following:

-   6α,9α-Difluoro-11β-hydroxy-16α-methyl-17α-(1-methylcyclobutylcarbonyl)oxy-3-oxo-androsta-1,4-diene-17β-carbothioic    acid S-fluoromethyl ester.

The compounds of formula (I) have potentially beneficialanti-inflammatory or anti-allergic effects, particularly upon topicaladministration, demonstrated by, for example, their ability to bind tothe glucocorticoid receptor and to illicit a response via that receptorwith long lasting effect. Hence, the compounds of formula (I) are usefulin the treatment of inflammatory and/or allergic disorders, especiallyin once-per-day therapy.

Examples of disease states in which the compounds of the invention haveutility include skin diseases such as eczema, psoriasis, allergicdermatitis neurodermatitis, pruritis and hypersensitivity reactions;inflammatory conditions of the nose, throat or lungs such as asthma(including allergen-induced asthmatic reactions), rhinitis (includinghayfever), nasal polyps, chronic obstructive pulmonary disease,interstitial lung disease, and fibrosis; inflammatory bowel conditionssuch as ulcerative colitis and Crohn's disease; and auto-immune diseasessuch as rheumatoid arthritis.

Compounds of the invention may also have use in the treatment ofconjunctiva and conjunctivitis.

It will be appreciated by those skilled in the art that reference hereinto treatment extends to prophylaxis as well as the treatment ofestablished conditions.

As mentioned above, compounds of formula (I) are useful in human orveterinary medicine, in particular as anti-inflammatory andanti-allergic agents, especially in once-per-day therapy.

There is thus provided as a further aspect of the invention a compoundof formula (I) or a physiologically acceptable solvate thereof for usein human or veterinary medicine, particularly in the treatment ofpatients with inflammatory and/or allergic conditions. Pharmaceuticalcompositions for once-per-day administration are of particular interest.

According to another aspect of the invention, there is provided the useof a compound of formula (I) or physiologically acceptable solvatethereof for the manufacture of a medicament for the treatment ofpatients with inflammatory and/or allergic conditions, especially fortherapy once-per-day.

In a further or alternative aspect, there is provided a method for thetreatment of a human or animal subject with an inflammatory and/orallergic condition, which method comprises administering to said humanor animal subject an effective amount of a compound of formula (I) orphysiologically acceptable solvate thereof, especially administrationonce-per-day.

The compounds according to the invention may be formulated foradministration in any convenient way, and the invention therefore alsoincludes within its scope pharmaceutical compositions comprising acompound of formula (I) or physiologically acceptable solvate thereoftogether, if desirable, in admixture with one or more physiologicallyacceptable diluents or carriers.

Further, there is provided a process for the preparation of suchpharmaceutical compositions which comprises mixing the ingredients.

The compounds according to the invention may, for example, be formulatedfor oral, buccal, sublingual, parenteral, local or rectaladministration, especially local administration.

Local administration as used herein, includes administration byinsufflation and inhalation. Examples of various types of preparationfor local administration include ointments, lotions, creams, gels,foams, preparations for delivery by transdermal patches, powders,sprays, aerosols, capsules or cartridges for use in an inhaler orinsufflator or drops (e.g. eye or nose drops), solutions/suspensions fornebulisation, suppositories, pessaries, retention enemas and chewable orsuckable tablets or pellets (e.g. for the treatment of aphthous ulcers)or liposome or microencapsulation preparations.

Advantageously compositions for topical administration to the lunginclude dry powder compositions and spray compositions.

Dry powder compositions for topical delivery to the lung may, forexample, be presented in capsules and cartridges for use in an inhaleror insufflator of, for example, gelatine. Formulations generally containa powder mix for inhalation of the compound of the invention and asuitable powder base such as lactose or starch. Use of lactose ispreferred. Each capsule or cartridge may generally contain between 20μg-10 mg of the compound of formula (I) optionally in combination withanother active ingredient. Alternatively, the compound of the inventionmay be presented without excipients. Packaging of the formulation may besuitable for unit dose or multi-dose delivery. In the case of multi-dosedelivery, the formulation can be pre-metered (eg as in Diskus, see GB2242134 or Diskhaler, see GB 2178965, 2129691 and 2169265) or metered inuse (eg as in Turbuhaler, see EP 69715). An example of a unit-dosedevice is Rotahaler (see GB 2064336). The Diskus inhalation devicecomprises an elongate strip formed from a base sheet having a pluralityof recesses spaced along its length and a lid sheet hermetically butpeelably sealed thereto to define a plurality of containers, eachcontainer having therein an inhalable formulation containing a compoundof formula (I) preferably combined with lactose. Preferably, the stripis sufficiently flexible to be wound into a roll. The lid sheet and basesheet will preferably have leading end portions which are not sealed toone another and at least one of the said leading end portions isconstructed to be attached to a winding means. Also, preferably thehermetic seal between the base and lid sheets extends over their wholewidth. The lid sheet may preferably be peeled from the base sheet in alongitudinal direction from a first end of the said base sheet.

Pharmaceutical formulations which are non-pressurised and adapted to beadministered as a dry powder topically to the lung via the buccal cavity(especially those which are free of excipient or are formulated with adiluent or carrier such as lactose or starch, most especially lactose)are of particular interest.

Spray compositions may for example be formulated as aqueous solutions orsuspensions or as aerosols delivered from pressurised packs, such as ametered dose inhaler, with the use of a suitable liquefied propellant.Aerosol compositions suitable for inhalation can be either a suspensionor a solution and generally contain the compound of formula (I) and asuitable propellant such as a fluorocarbon or hydrogen-containingchlorofluorocarbon or mixtures thereof, particularly hydrofluoroalkanes,especially 1,1,1,2-tetrafluoroethane,1,1,1,2,3,3,3-heptafluoro-n-propane or a mixture thereof. The aerosolcomposition may optionally contain additional formulation excipientswell known in the art such as surfactants eg oleic acid or lecithin andcosolvents eg ethanol. One example formulation is excipient free andconsists essentially of (eg consists of) compound of formula (I)(preferably in unsolvated form eg as Form 1) (optionally in combinationwith another therapeutically active ingredient) and a propellantselected from 1,1,1,2-tetrafluoroethane,1,1,1,2,3,3,3-heptafluoro-n-propane and mixture thereof. Another exampleformulation comprises particulate compound of formula (I), a propellantselected from 1,1,1,2-tetrafluoroethane,1,1,1,2,3,3,3-heptafluoro-n-propane and mixture thereof and a suspendingagent which is soluble in the propellant eg an oligolactic acid orderivative thereof as described in WO94/21229. The preferred propellantis 1,1,1,2-tetrafluoroethane. As noted elsewhere in this specification,compound of formula (I) does not appear to form a solvate with1,1,1,2-tetrafluoroethane. Pressurised formulations will generally beretained in a canister (eg an aluminium canister) closed with a valve(eg a metering valve) and fitted into an actuator provided with amouthpiece.

Medicaments for administration by inhalation desirably have a controlledparticle size. The optimum particle size for inhalation into thebronchial system is usually 1–10 μm, preferably 2–5 μm. Particles havinga size above 20 μm are generally too large when inhaled to reach thesmall airways. To achieve these particle sizes the particles of compoundof formula (I) as produced may be size reduced by conventional means egby micronisation. The desired fraction may be separated out by airclassification or sieving. Preferably, the particles will becrystalline, prepared for example by a process which comprises mixing ina continuous flow cell in the presence of ultrasonic radiation a flowingsolution of compound of formula (I) as medicament in a liquid solventwith a flowing liquid antisolvent for said medicament (eg as describedin International Patent Application PCT/GB99/04368) or else by a processwhich comprises admitting a stream of solution of the substance in aliquid solvent and a stream of liquid antisolvent for said substancetangentially into a cylindrical mixing chamber having an axial outletport such that said streams are thereby intimately mixed throughformation of a vortex and precipitation of crystalline particles of thesubstance is thereby caused (eg as described in International PatentApplication PCT/GB00/04327). When an excipient such as lactose isemployed, generally, the particle size of the excipient will be muchgreater than the inhaled medicament within the present invention. Whenthe excipient is lactose it will typically be present as milled lactose,wherein not more than 85% of lactose particles will have a MMD of 60–90μm and not less than 15% will have a MMD of less than 15 μm.

Formulations for administration topically to the nose (eg for thetreatment of rhinitis) include pressurised aerosol formulations andaqueous formulations administered to the nose by pressurised pump.Formulations which are non-pressurised and adapted to be administeredtopically to the nasal cavity are of particular interest. Theformulation preferably contains water as the diluent or carrier for thispurpose. Aqueous formulations for administration to the lung or nose maybe provided with conventional excipients such as buffering agents,tonicity modifying agents and the like. Aqueous formulations may also beadministered to the nose by nebulisation.

Other possible presentations include the following:

Ointments, creams and gels, may, for example, be formulated with anaqueous or oily base with the addition of suitable thickening and/orgelling agent and/or solvents. Such bases may thus, for example, includewater and/or an oil such as liquid paraffin or a vegetable oil such asarachis oil or castor oil, or a solvent such as polyethylene glycol.Thickening agents and gelling agents which may be used according to thenature of the base include soft paraffin, aluminium stearate,cetostearyl alcohol, polyethylene glycols, woolfat, beeswax,carboxypolymethylene and cellulose derivatives, and/or glycerylmonostearate and/or non-ionic emulsifying agents.

Lotions may be formulated with an aqueous or oily base and will ingeneral also contain one or more emulsifying agents, stabilising agents,dispersing agents, suspending agents or thickening agents.

Powders for external application may be formed with the aid of anysuitable powder base, for example, talc, lactose or starch. Drops may beformulated with an aqueous or non-aqueous base also comprising one ormore dispersing agents, solubilising agents, suspending agents orpreservatives.

Advantageously, the formulations of the invention may be buffered by theaddition of suitable buffering agents.

The proportion of the active compound of formula (I) in the localcompositions according to the invention depends on the precise type offormulation to be prepared but will generally be within the range offrom 0.001 to 10% by weight. Generally, however for most types ofpreparations advantageously the proportion used will be within the rangeof from 0.005 to 1% and preferably 0.01 to 0.5%. However, in powders forinhalation or insufflation the proportion used will be within the rangeof from 0.1 to 5%.

Aerosol formulations are preferably arranged so that each metered doseor “puff” of aerosol contains 20 μg–2000 μg, preferably about 20 μg–500μg of a compound of formula (I). Administration may be once daily orseveral times daily, for example 2, 3, 4 or 8 times, giving for example1, 2 or 3 doses each time. The overall daily dose with an aerosol willbe within the range 100 μg-10 mg preferably, 200 μg–2000 μg. The overalldaily dose and the metered dose delivered by capsules and cartridges inan inhaler or insufflator will generally be double those with aerosolformulations.

Topical preparations may be administered by one or more applications perday to the affected area; over skin areas occlusive dressings mayadvantageously be used. Continuous or prolonged delivery may be achievedby an adhesive reservoir system.

For internal administration the compounds according to the inventionmay, for example, be formulated in conventional manner for oral,parenteral or rectal administration. Formulations for oraladministration include syrups, elixirs, powders, granules, tablets andcapsules which typically contain conventional excipients such as bindingagents, fillers, lubricants, disintegrants, wetting agents, suspendingagents, emulsifying agents, preservatives, buffer salts, flavouring,colouring and/or sweetening agents as appropriate. Dosage unit formsare, however, preferred as described below.

Preferred forms of preparation for internal administration are dosageunit forms i.e. tablets and capsules. Such dosage unit forms containfrom 0.1 mg to 20 mg preferably from 2.5 to 10 mg of the compounds ofthe invention.

The compounds according to the invention may in general may be given byinternal administration in cases where systemic adreno-cortical therapyis indicated.

In general terms preparations, for internal administration may containfrom 0.05 to 10% of the active ingredient dependent upon the type ofpreparation involved. The daily dose may vary from 0.1 mg to 60 mg, e.g.5–30 mg, dependent on the condition being treated, and the duration oftreatment desired.

Slow release or enteric coated formulations may be advantageous,particularly for the treatment of inflammatory bowel disorders.

The pharmaceutical compositions according to the invention may also beused in combination with another therapeutically active agent, forexample, a β₂ adrenoreceptor agonist, an anti-histamine or ananti-allergic. The invention thus provides, in a further aspect, acombination comprising a compound of formula (I) or a physiologicallyacceptable solvate thereof together with another therapeutically activeagent, for example, a β₂-adrenoreceptor agonist, an anti-histamine, ananti-allergic or an anti-cholinergic.

Examples of β₂-adrenoreceptor agonists include salmeterol (eg asxinafoate), salbutamol (eg as sulphate), formoterol (eg as fumarate),fenoterol or terbutaline (eg as sulphate). Long-acting β₂-adrenoreceptoragonists are preferred, especially those having a therapeutic effectover a 24 hour period.

Especially preferred long-acting β₂ adrenoreceptor agonists arecompounds of formula (X)

or a salt or solvate thereof, wherein:

-   m is an integer of from 2 to 8;-   n is an integer of from 3 to 11, preferably from 3 to 7;-   with the proviso that m+n is 5 to 19, preferably 5 to 12;-   R¹¹ is —XSO₂NR¹⁶R¹⁷-   wherein X is —(CH₂)_(p)— or C₂₋₆ alkenylene;-   R¹⁶ and R¹⁷ are independently selected from hydrogen, C₁₋₆alkyl,    C₃₋₇cycloalkyl, C(O)NR¹⁸R¹⁹, phenyl, and phenyl(C₁₋₄alkyl)-,-   or R¹⁶ and R⁷, together with the nitrogen to which they are bonded,    form a 5-, 6-, or 7-membered nitrogen containing ring, and R¹⁶ and    R¹⁷ are each optionally substituted by one or two groups selected    from halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, hydroxy-substituted    C₁₋₆alkoxy, —CO₂R¹⁸, —SO₂NR¹⁸R¹⁹, —CONR¹⁸R¹⁹, —NR¹⁸C(O)R¹⁹, or a 5-,    6- or 7-membered heterocylic ring;-   R¹⁸ and R¹⁹ are independently selected from hydrogen, C₁₋₆alkyl,-   C₃₋₆cycloalkyl, phenyl, and phenyl(C₁₋₄alkyl)-; and-   p is an integer of from 0 to 6, preferably from 0 to 4;-   R¹² and R¹³ are independently selected from hydrogen, C₁₋₆alkyl,    C₁₋₆alkoxy, halo, phenyl, and C₁₋₆haloalkyl; and-   R¹⁴ and R¹⁵ are independently selected from hydrogen and C₁₋₄alkyl    with the proviso that the total number of carbon atoms in R¹⁴ and    R¹⁵ is not more than 4.

In the compounds of formula (I) the group R¹¹ is preferably attached tothe meta-position relative to the —O—(CH₂)_(n)— link.

-   R¹¹ preferably represents —SO₂NR¹⁶R¹⁷ wherein R¹⁶ and R¹⁷ are    independently selected from hydrogen and C₁₋₆alkyl, more preferably    R¹¹ is —SO₂NH₂.-   R¹⁴ and R¹⁵ are preferably independently selected from hydrogen and    methyl, more preferably R¹⁴ and R¹⁵ are both hydrogen.-   m is suitably 4, 5, or 6, and n is suitably 3, 4, 5 or 6. Preferably    m is 5 or 6 and n is 3 or 4, such that m+n is 8, 9 or 10, preferably    9.

More especially preferred compounds of formula (X) are compounds offormula (Xa)

or a salt or solvate thereof, wherein

-   R¹¹ is as defined above for formula (X).

Further more especially preferred compounds of formula (X) are compoundsof formula (Xb):

or a salt or solvate thereof, wherein

-   R¹¹ is as defined above for formula (X).

In the compounds of formulae (Xa) and (Xb), the group R¹¹ is preferablyattached to the meta-position relative to the —O—(CH₂)_(n)—, —O—(CH₂)₄—or —O—(CH₂)₃— link respectively.

In the compounds of formulae (Xa) and (Xb), R¹¹ is preferably—SO₂NR¹⁶R¹⁷ wherein R¹⁶ and R¹⁷ are independently selected from hydrogenand C₁₋₆alkyl, more preferably R¹¹ is —SO₂NH₂.

In the definition of R¹¹ where ‘R¹⁶ and R¹⁷ together with the nitrogenatom to which they are bonded, form a 5-, 6-, or 7-membered nitrogencontaining ring’, the term “5-, 6-, or 7-membered nitrogen containingring” means a 5-, 6-, or 7-membered saturated or unsaturated ring whichincludes the sulfonamide nitrogen atom and optionally 1 or 2 otherheteroatoms independently selected from nitrogen, sulphur, and oxygen.Suitable examples of such a ring include piperidinyl, morpholinyl, andpiperazinyl.

In the definition of R¹¹, specifically the optional substituents on R¹⁶and R¹⁷, the term “5-, 6-, or 7-membered heterocyclic ring” means a 5-,6-, or 7-membered fully or partially saturated or unsaturated ring whichincludes 1, 2, 3 or 4 heteroatoms independently selected from nitrogen,sulphur, and oxygen. Suitable examples of such a ring include pyrrolyl,furyl, thienyl, pyridinyl, pyrazinyl, pyridazinyl, imidazolyl,tetrazolyl, tetrahydrofuranyl, oxazolyl, thiazolyl, thiadiazolyl,piperidinyl, morpholinyl, and piperazinyl.

In the definition of X, the term “alkenylene” includes both cis andtrans structures. Suitable examples of alkenylene groups include—CH═CH—.

The compounds of formulae (X), (Xa) and (Xb) include an asymmetriccentre, namely the carbon atom of the

group. The present invention includes both (S) and (R) enantiomerseither in substantially pure form or admixed in any proportions.

Similarly, where R¹⁴ and R¹⁵ are different groups, the carbon atom towhich they are attached is an asymmetric centre and the presentinvention includes both (S) and (R) enantiomers at this centre either insubstantially pure form or admixed in any proportions.

Thus the compounds of formulae (X), (Xa) and (Xb) include allenantiomers and diastereoisomers as well as mixtures thereof in anyproportions.

The most preferred compound of formula (X) is3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-hexyl]oxy}butyl)benzenesulfonamideor a salt or solvate thereof.

Salts and solvates of compounds of formulae (X), (Xa) and (Xb) which aresuitable for use in medicine are those wherein the counterion orassociated solvent is pharmaceutically acceptable. However, salts andsolvates having non-pharmaceutically acceptable counterions orassociated solvents are within the scope of the present invention, forexample, for use as intermediates in the preparation of other compoundsof formulae (X), (Xa) and (Xb) and their pharmaceutically acceptablesalts and solvates.

Suitable salts according to the invention include those formed with bothorganic and inorganic acids or bases. Pharmaceutically acceptable acidaddition salts include those formed from hydrochloric, hydrobromic,sulphuric, citric, tartaric, phosphoric, lactic, pyruvic, acetic,trifluoroacetic, triphenylacetic, sulphamic, sulphanilic, succinic,oxalic, fumaric, maleic, malic, glutamic, aspartic, oxaloacetic,methanesulphonic, ethanesulphonic, arylsulphonic (for examplep-toluenesulphoriic, benzenesulphonic, naphthalenesulphonic ornaphthalenedisulphonic), salicylic, glutaric, gluconic, tricarballylic,cinnamic, substituted cinnamic (for example, phenyl, methyl, methoxy orhalo substituted cinnamic, including 4-methyl and 4-methoxycinnamicacid), ascorbic, oleic, naphthoic, hydroxynaphthoic (for example 1- or3-hydroxy-2-naphthoic), naphthaleneacrylic (for examplenaphthalene-2-acrylic), benzoic, 4-methoxybenzoic, 2- or4-hydroxybenzoic, 4-chlorobenzoic, 4-phenylbenzoic, benzeneacrylic (forexample 1,4-benzenediacrylic) and isethionic acids. Pharmaceuticallyacceptable base salts include ammonium salts, alkali metal salts such asthose of sodium and potassium, alkaline earth metal salts such as thoseof calcium and magnesium and salts with organic bases such asdicyclohexyl amine and N-methyl-D-glucamine.

Compounds of formula (X), (Xa) and (Xb) may be prepared by reference toExample X recited below, by analogous processes, or by otherconventional processes known per se.

Since the compounds of formula (I) are long-acting, preferably thecomposition comprising the compound of formula (I) and the long-actingβ₂-adrenoreceptor agonists will be delivered once-per-day and the doseof each will be selected so that the composition has a therapeuticeffect in the treatment of respiratory disorders effect (eg in thetreatment of asthma or COPD, particularly asthma) over 24 hours or more.

Examples of anti-histamines include methapyrilene or loratadine.Examples of anti-allergics include cromoglycate (eg as sodium),ketotifen and nedocromil (as as sodium). Examples of anti-cholinergicsinclude ipratropium (eg as bromide), tiotropium, atropine or oxitropium.Any of the aforementioned substances may be employed in the form ofalternative salts or solvates thereof.

Other suitable combinations include, for example, otheranti-inflammatory agents eg. NSAIDs (eg. PDE4 inhibitors, leukotrieneantagonists, iNOS inhibitors, tryptase and elastase inhibitors, beta-2integrin antagonists and adenosine 2a agonists)) or antinfective agents(eg. antibiotics, antivirals).

Of particular interest is use of the compounds of formula (I) incombination with a phosphodiesterase 4 (PDE4) inhibitor. ThePDE4-specific inhibitor useful in this aspect of the invention may beany compound that is known to inhibit the PDE4 enzyme or which isdiscovered to act as a PDE4 inhibitor, and which are only PDE4inhibitors, not compounds which inhibit other members of the PDE familyas well as PDE4. Generally it is preferred to use a PDE4 Inhibitor whichhas an IC₅₀ ratio of about 0.1 or greater as regards the IC₅₀ for thePDE4 catalytic form which binds rolipram with a high affinity divided bythe IC₅₀ for the form which binds rolipram with a low affinity. For thepurposes of this disclosure, the cAMP catalytic site which binds R and Srolipram with a low affinity is denominated the “low affinity” bindingsite (LPDE 4) and the other form of this catalytic site which bindsrolipram with a high affinity is denominated the “high affinity” bindingsite (HPDE 4). This term “HPDE4” should not be confused with the term“hPDE4” which is used to denote human PDE4. Initial experiments wereconducted to establish and validate a [³H]-rolipram binding assay.Details of this work are given in the Binding Assays described in detailbelow.

The preferred PDE4 inhibitors of use in this invention will be thosecompounds which have a salutary therapeutic ratio, i.e., compounds whichpreferentially inhibit cAMP catalytic activity where the enzyme is inthe form that binds rolipram with a low affinity, thereby reducing theside effects which apparently are linked to inhibiting the form whichbinds rolipram with a high affinity. Another way to state this is thatthe preferred compounds will have an IC₅₀ ratio of about 0.1 or greateras regards the IC₅₀ for the PDE4 catalytic form which binds rolipramwith a high affinity divided by the IC₅₀ for the form which bindsrolipram with a low affinity. A further refinement of this standard isthat of one wherein the PDE4 inhibitor has an IC₅₀ ratio of about 0.1 orgreater; said ratio is the ratio of the IC₅₀ value for competing withthe binding of 1 nM of [³H]R-rolipram to a form of PDE4 which bindsrolipram with a high affinity over the IC₅₀ value for inhibiting thePDE4 catalytic activity of a form which binds rolipram with a lowaffinity using 1 μM[³H]-cAMP as the substrate.

Examples of useful PDE4 inhibitors are:

-   (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone;-   (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone;-   3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N′-[N2-cyano-S-methyl-isothioureido]benzyl)-2-pyrrolidone;-   cis    4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylic    acid];-   cis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol];-   (R)-(+)-ethyl    [4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-ylidene]acetate;    and-   (S)-(−)-ethyl    [4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-ylidene]acetate.

Most preferred are those PDE4 inhibitors which have an IC₅₀ ratio ofgreater than 0.5, and particularly those compounds having a ratio ofgreater than 1.0. Preferred compounds are cis4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylicacid,2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-oneandcis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol];these are examples of compounds which bind preferentially to the lowaffinity binding site and which have an IC₅₀ ratio of 0.1 or greater.

Other compounds of interest include:

Compounds set out in U.S. Pat. No. 5,552,438 issued 3 Sep. 1996; thispatent and the compounds it discloses are incorporated herein in full byreference. The compound of particular interest, which is disclosed inU.S. Pat. No. 5,552,438, iscis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylicacid (also known as cilomalast) and its salts, esters, pro-drugs orphysical forms;

AWD-12-281 from Astra (Hofgen, N. et al. 15th EFMC Int Symp Med Chem(September 6–10, Edinburgh) 1998, Abst P. 98); a 9-benzyladeninederivative nominated NCS-613 (INSERM); D-4418 from Chiroscience andSchering-Plough; a benzodiazepine PDE4 inhibitor identified as Cl-1018(PD-168787; Parke-Davis/Warner-Lambert); a benzodioxole derivative KyowaHakko disclosed in WO 9916766; V-11294A from Napp (Landells, L. J. etal. Eur Resp J [Annu Cong Eur Resp Soc (September 19–23, Geneva) 1998]1998, 12(Suppl. 28): Abst P2393); roflumilast (CAS reference No162401-32-3) and a pthalazinone (WO 9947505) from Byk-Gulden; or acompound identified as T-440 (Tanabe Seiyaku; Fuji, K. et al. JPharmacol Exp Ther, 1998, 284(1): 162).

Phosphodiesterase and Rolipram Binding Assays

Assay Method 1A

Isolated human monocyte PDE4 and hrPDE (human recombinant PDE4) wasdetermined to exist primarily in the low affinity form. Hence, theactivity of test compounds against the low affinity form of PDE4 can beassessed using standard assays for PDE4 catalytic activity employing 1μM [³H]cAMP as a substrate (Torphy et al., J. of Biol. Chem., Vol. 267,No. 3 pp 1798–1804, 1992).

Rat brain high speed supernatants were used as a source of protein andboth enantiomers of [³H]-rolipram were prepared to a specific activityof 25.6 Ci/mmol. Standard assay conditions were modified from thepublished procedure to be identical to the PDE assay conditions, exceptfor the last of the cAMP: 50 mM Tris HCl (pH 7.5), 5 mM MgCl₂, 50 μM5′-AMP and 1 nM of [³H]-rolipram (Torphy et al., J. of Biol. Chem., Vol.267, No. 3 pp 1798–1804, 1992). The assay was run for 1 hour at 30° C.The reaction was terminated and bound ligand was separated from freeligand using a Brandel cell harvester. Competition for the high affinitybinding site was assessed under conditions that were identical to thoseused for measuring low affinity PDE activity, expect that [³H]-cAMP wasnot present.

Assay Method 1B

Measurement of Phosphodiesterase Activity

PDE activity was assayed using a [³H]cAMP SPA or [³H]cGMP SPA enzymeassay as described by the supplier (Amersham Life Sciences). Thereactions were conducted in 96-well plates at room temperature, in 0.1ml of reaction buffer containing (final concentrations): 50 mM Tris-HCl,pH 7.5, 8.3 mM MgCl₂, 1.7 mM EGTA, [³H]cAMP or [³H] cGMP (approximately2000 dpm/pmol), enzyme and various concentrations of the inhibitors. Theassay was allowed to proceed for 1 hr and was terminated by adding 50 μlof SPA yttrium silicate beads in the presence of zinc sulfate. Theplates were shaken and allowed to stand at room temperature for 20 min.Radiolabeled product formation was assessed by scintillationspectrometry.

[³H]R-Rolipram Binding Assay

The [³H]R-rolipram binding assay was performed by modification of themethod of Schneider and co-workers, see Nicholson, et al., TrendsPharmacol. Sci., Vol. 12, pp. 19–27 (1991) and McHale et al., Mol.Pharmacol., Vol. 39, 109–113 (1991). R-Rolipram binds to the catalyticsite of PDE4 see Torphy et al., Mol. Pharmacol., Vol. 39, pp. 376–384(1991). Consequently, competition for [³H]R-rolipram binding provides anindependent confirmation of the PDE4 inhibitor potencies of unlabeledcompetitors. The assay was performed at 30° C. for 1 hr in 0.5 μl buffercontaining (final concentrations): 50 mM Tris-HCl, pH 7.5, 5 mM MgCl₂,0.05% bovine serum albumin, 2 nM [³H]R-rolipram (5.7×104 dpm/pmol) andvarious concentrations of non-radiolabeled inhibitors. The reaction wasstopped by the addition of 2.5 ml of ice-cold reaction buffer (without[³H]-R-rolipram) and rapid vacuum filtration (Brandel Cell Harvester)through Whatman GF/B filters that had been soaked in 0.3%polyethylenimine. The filters were washed with an additional 7.5 ml ofcold buffer, dried, and counted via liquid scintillation spectrometry.

The invention thus provides, in a further aspect, a combinationcomprising a compound of formula (I) or a physiologically acceptablesolvate thereof together with a PDE4 inhibitor.

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical formulation and thus pharmaceuticalformulations comprising a combination as defined above together with apharmaceutically acceptable diluent or carrier represent a furtheraspect of the invention.

The individual compounds of such combinations may be administered eithersequentially or simultaneously in separate or combined pharmaceuticalformulations. Appropriate doses of known therapeutic agents will bereadily appreciated by those skilled in the art.

The compounds of formula (I) and solvates thereof may be prepared by themethodology described hereinafter, constituting a further aspect of thisinvention.

A process according to the invention for preparing a compound of formula(I) comprises alkylation of a thioacid of formula (II)

wherein R², R³, R⁴, R⁵ and

are as defined above.

In this process the compound of formula (II) may be reacted with, forexample, an appropriate alkyl or haloalkyl halide under standardconditions.

When R₁ represents fluoromethyl, the preferred haloalkyl halide reagentis bromofluoromethane.

Compounds of formula (II) may be prepared from the corresponding17α-hydroxyl derivative of formula (III):

wherein R², R³, R⁴, R⁵ and

are as defined above, using for example, the methodology described by G.H. Phillipps et al., (1994) Journal of Medicinal Chemistry, 37,3717–3729. For example the compound of formula (III) may be reacted witha compound of formula R₂COOH or an activated derivative thereof eg anactivated ester, anhydride or halide (eg the acid chloride). Thereaction may be performed in the presence of an organic solvent egtriethylamine, usually together with dimethylaminopyridine (DMAP).

Compounds of formula (III) may be prepared in accordance with proceduresdescribed in GB 2088877B. Compounds of formula (III) may also beprepared by a process comprising the following steps:

Step (a) comprises oxidation of a solution containing the compound offormula (IV). Preferably, step (a) will be performed in the presence ofa solvent comprising methanol, water, tetrahydrofuran, dioxan ordiethylene glygol dimethylether. For example, so as to enhance yield andthroughput, preferred solvents are methanol, water or tetrahydrofuran,and more preferably are water or tetrahydrofuran, especially water andtetrahydrofuran as solvent. Dioxan and diethylene glygol dimethyletherare also preferred solvents which may optionally (and preferably) beemployed together with water. Preferably, the solvent will be present inan amount of between 3 and 10 vol relative to the amount of the startingmaterial (1 wt.), more preferably between 4 and 6 vol., especially 5vol. Preferably the oxidising agent is present in an amount of 1–9 molarequivalents relative to the amount of the starting material. Forexample, when a 50% w/w aqueous solution of periodic acid is employed,the oxidising agent may be present in an amount of between 1.1 and 10wt. relative to the amount of the starting material (1 wt.), morepreferably between 1.1 and 3 wt., especially 1.3 wt. Preferably, theoxidation step will comprise the use of a chemical oxidising agent. Morepreferably, the oxidising agent will be periodic acid or iodic acid or asalt thereof. Most preferably, the oxidising agent will be periodic acidor sodium periodate, especially periodic acid. Alternatively (or inaddition), it will also be appreciated that the oxidation step maycomprise any suitable oxidation reaction, eg. one which utilises airand/or oxygen. When the oxidation reaction utilises air and/or oxygen,the solvent used in said reaction will preferably be methanol.Preferably, step (a) will involve incubating the reagents at roomtemperature or a little warmer, say around 25° C. eg for 2 hours. Thecompound of formula (V) may be isolated by recrystallisation from thereaction mixture by addition of an anti-solvent. A suitable anti-solventfor compound of formula (V) is water. Surprisingly we have discoveredthat it is highly desirable to control the conditions under which thecompound of formula (V) is precipitated by addition of anti-solvent egwater. When the recrystallisation is performed using chilled water (egwater/ice mixture at a temperature of 0–50° C.) although betteranti-solvent properties may be expected we have found that thecrystalline product produced is very voluminous, resembles a soft geland is very difficult to filter. Without being limited by theory webelieve that this low density product contains a large amount ofsolvated solvent within the crystal lattice By contrast when conditionsof around 10° C. or higher are used (eg around ambient temperature) agranular product of a sand like consistency which is very easilyfiltered is produced. Under these conditions, crystallisation typicallycommences after around 1 hour and is typically completed within a fewhours (eg 2 hours). Without being limited by theory we believe that thisgranular product contains little or no of solvated solvent within thecrystal lattice.

Step (b) will typically comprise the addition of a reagent suitable forconverting a carboxylic acid to a carbothioic acid eg. using hydrogensulphide gas together with a suitable coupling agent eg.carbonyldiimidazole (CDI) in the presence of a suitable solvent eg.dimethylformamide.

Solvates of compounds of formula (I) which are not physiologicallyacceptable may be useful as intermediates in the preparation ofcompounds of formula (I) or physiologically acceptable solvates thereof.

The advantages of compounds of formula (I) and/or solvates thereof mayinclude the fact that the substances appear to demonstrate excellentanti-inflammatory properties, with predictable pharmacokinetic andpharmacodynamic behaviour, with an attractive side-effect profile(demonstrated for example, by increased selectivity for theglucocorticoid receptor over the progesterone receptor and/or increasedselectivity for glucocorticoid receptor mediated transrepression overtransactivation) and are compatible with a convenient regime oftreatment in human patients. Further advantages may include the factthat the substances have desirable physical and chemical propertieswhich allow for ready manufacture and storage.

The following non-limiting Examples illustrate the invention:

EXAMPLES

General

LCMS was conducted on a Supelcosil LCABZ+PLUS column (3.3 cm×4.6 mm ID)eluting with 0.1% HCO₂H and 0.01 M ammonium acetate in water (solventA), and 0.05% HCO₂H 5% water in acetonitrile (solvent B), using thefollowing elution gradient 0–0.7 min 0% B, 0.7–4.2 min 100% B, 4.2–5.3min 0% B, 5.3–5.5 min 0% B at a flow rate of 3 ml/min. The mass spectrawere recorded on a Fisons VG Plafform spectrometer using electrospraypositive and negative mode (ES+ve and ES−ve).

Intermediates

Intermediate 1:17α-(Cyclobutylcarbonyl)oxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid

A solution of6α,9α-difluoro-11β,17α-dihydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid (prepared in accordance with the procedure described in GB2088877B) (1 g, 2.42 mmol) in anhydrous dichloromethane (20 ml) andtriethylamine (0.88 ml, 6.32 mmol) was treated at <50° C. under nitrogenwith a solution of cyclobutanecarbonyl chloride (0.72 ml, 6.31 mmol) inanhydrous dichloromethane. (5 ml) over approximately 2 min. The solutionwas stirred at <5° C. for 45 min and then diluted with dichloromethane(20 ml) and washed successively with 5% sodium hydrogen carbonatesolution (20 m), 1 M hydrochloric acid (20 ml) and water (20 ml). Theorganic solution was dried (Na₂SO₄) and evaporated to give an off-whitefoam (1.47 g) which was dissolved in acetone (30 ml) and treated with1-methylpiperazine (1 ml, 9 mmol). After 2.5 h the solution was slowlyadded to a stirred mixture of 2M hydrochloric acid (55 ml) and ice (55ml) and the precipitate was collected and dried in vacuo to give thetitle compound as a white solid (1.12 g, 93.5%): LCMS retention time3.79 min, m/z 495 MH⁺

Intermediate 2:17α-(Cyclopentylcarbonyl)oxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid.

Prepared using methods similar to that described for Intermediate 1.LCMS retention time 4.00 min, m/z 509 MH⁺

Intermediate 3:17α-(Cyclohexylcarbonyl)oxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid

Prepared using methods similar to that described for Intermediate 1.LCMS retention time 4.17 min, m/z 523 MH⁺

Intermediate 4:17α-(Cyclopropylcarbonyl)oxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid

Prepared using methods similar to that described for Intermediate 1.LCMS retention time 3.65 min, m/z 481 MH⁺

Intermediate 5:6α,9α-Difluoro-11β-hydroxy-16α-methyl-17α-(1-methycyclopropylcarbonyl)oxy-3-oxo-androsta-1,4-diene-17β-carbothioicacid

Prepared using methods similar to that described for Intermediate 1.LCMS retention time 3.75 min, m/z 495 MH⁺

Intermediate 6:6α,9α-Difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(2,2,3,3-tetramethycyclopropylcarbonyl)oxy-androsta-1,4-diene-17β-carbothioicacid

Prepared using methods similar to that described for Intermediate 1.LCMS retention time 4.12 min, m/z 537 MH⁺

Intermediate 7:17α-(2,2-Dichloro-1-methycyclopropylcarbonyl)oxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid

Prepared using methods similar to that described for Intermediate 1.LCMS retention time 4.20 min, m/z 563,565 MH⁺

Intermediate 8:17α(2,2-Dichlorocylopropylcarbonyl)oxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17βcarbothioicacid

Prepared using methods similar to that described for Intermediate 1.LCMS retention time 4.14 min, m/z 549,551 MH⁺

Intermediate 9:6α,9α-Difluoro-11β-hydroxy-16α-methyl-17α-(3-methylenecyclobutylcarbonyl)oxy-3-oxo-androsta-1,4-diene-17β-carbothioicacid

Prepared using methods similar to that described for Intermediate 1.LCMS retention time 4.10 min, m/z 507 MH⁺

Intermediate 10:6α,9α-Difluoro-11β-hydroxy-16α-methyl-17α-(2-methylcyclopropylcarbonyl)oxy-3-oxo-androsta-1,4-diene-17β-carbothioicacid

Prepared using methods similar to that described for Intermediate 1.LCMS retention time 3.90 min, m/z 495 MH⁺

Intermediate 11:6α,9α-Difluoro-11β-hydroxy-16α-methyl-17α-(1-methylcyclobutylcarbonyl)oxy-3-oxo-androsta-1,4-diene-17β-carbothioicacid

Prepared using methods similar to that described for Intermediate 1.LCMS retention time 4.13 min, m/z 509 MH⁺

Intermediate 12:6α,9α-Difluoro-17α-(3,3-dimethylcyclobutylcarbonyl)oxy-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid

Prepared using methods similar to that described for Intermediate 1.LCMS retention time 4.09 min, m/z 523 MH⁺

Intermediate 13:6α,9α-Difluoro-17α-(3,3-difluorocyclobutylcarbonyl)oxy-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid

Prepared using methods similar to that described for Intermediate 1.LCMS retention time 3.78 min, m/z 531 MH⁺

Intermediate 14:6α,9α-Difluoro-11β-hydroxy-16α-methyl-17α-(1-methylcyclopentylcarbonyl)oxy-3-oxo-androsta-1,4-diene-17β-carbothioicacid

Prepared using methods similar to that described for Intermediate 1.LCMS retention time 4.05 min, m/z 523 MH+

Intermediate 15:6α,9α-Difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(3-oxocyclobutylcarbonyl)oxy-androsta-1,4-diene-17β-carbothioicacid

Prepared using methods similar to that described for Intermediate 1.LCMS retention time 3.41 min, m/z 509 MH⁺

EXAMPLES Example 117α-(Cyclobutylcarbonyl)oxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester

Sodium hydrogen carbonate (112 mg, 1.33 mmol) was added to a solution ofIntermediate 1 (600 mg, 1.21 mmol) in anhydrous N,N-dimethylformamide (6ml) and the mixture cooled to −20° C. under nitrogen. Bromofluoromethane(0.15 ml, 2.7 mmol) was added and the mixture was stirred at −20° C. for2 h. Diethylamine (0.6 ml, 5.8 mmol) was added and the mixture stirredat −20° C. for 15 min and then added to vigorously stirred 2Mhydrochloric acid (25 ml). Water (75 ml) was added and after stirringfor a further 30 min the white precipitate was collected and dried invacuo (606 mg). This material was purified was column chromatography onsilica gel to give the title compound as a white solid (520 mg, 81%):LCMS retention time 3.67 min, m/z 527 MH⁺.

Example 217α-(Cyclopentylcarbonyl)oxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester

Prepared from Intermediate 2 using methods similar to that described forExample 1 LCMS retention time 3.92 min, m/z 541 MH⁺

Example 317α-(Cyclohexylcarbonyl)oxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester

Prepared from Intermediate 3 using methods similar to that described forExample 1 LCMS retention time 4.02 min, m/z 555 MH⁺

Example 417α-(Cyclopropylcarbonyl)oxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester

Prepared from Intermediate 4 using methods similar to that described forExample 1 LCMS retention time 3.54 min, m/z 513 MH⁺

Example 56α,9α-Difluoro-11β-hydroxy-16α-methyl-17α-(1-methycyclopropylcarbonyl)oxy-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester

Prepared from Intermediate 5 using methods similar to that described forExample 1 LCMS retention time 3.66 min, m/z 527 MH+

Example 66α,9α-Difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(2,2,3,3-tetramethycyclopropylcarbonyl)oxy-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester

Prepared from Intermediate 6 using methods similar to that described forExample 1 LCMS retention time 4.02 min, m/z 569 MH⁺

Example 717α-(2,2-Dichloro-1-methycyclopropylcarbonyl)oxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester

Prepared from Intermediate 7 using methods similar to that described forExample 1 LCMS retention time 3.79 min, m/z 595, 597, 599 MH⁺

Example 817α-(2,2-Dichlorocylopropylcarbonyl)oxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester

Prepared from Intermediate 8 using methods similar to that described forExample 1 LCMS retention time 3.68 min, m/z 581, 583 MH⁺

Example 9 6α,9α-Difluoro-11β-hydroxy-16α-methyl-17α-(3-methylenecyclobutylcarbonyl)oxy-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester

Prepared from Intermediate 9 using methods similar to that described forExample 1 LCMS retention time 3.68 min, m/z 539 MH⁺

Example 106α,9α-Difluoro-11β-hydroxy-16α-methyl-17α-(2-methylcyclopropylcarbonyl)oxy-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester

Prepared from Intermediate 10 using methods similar to that describedfor Example 1. LCMS retention time 3.57 min, m/z 527 MH⁺

Example 116α,9α-Difluoro-11β-hydroxy-16α-methyl-17α-(1-methylcyclobutylcarbonyloxy-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester

Prepared from Intermediate 11 using methods similar to that describedfor Example 1. LCMS retention time 3.73 min, m/z 541 MH⁺

Example 126α,9α-Difluoro-17α-(3,3-dimethylcyclobutylcarbonyl)oxy-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester

Water (1.8 ml), benzyltributylammonium chloride (35 mg) anddiisopropylethylamine (0.21 ml) were added to a stirred and cooled (0°C.) solution of Intermediate 12 (585 mg, 1.12 mmol) in ethyl acetate (15ml). A solution of bromofluoromethane (0.075 ml) in ethyl acetate (0.75ml) was added and the mixture stirred at room temperature for 18 h. Asolution of 2% diethylamine in 4:1 acetonitrile:water (1 ml) was addedand the mixture stirred for 10 min. The organic phase was separated,washed successively with 0.5M hydrochloric acid, water and 1% sodiumbicarbonte solution and dried and evaporated. The residue (570 mg) waspurified by preparative HPLC to give the title compound as a cream solid(490 mg, 79%): LCMS retention time 3.75 min, m/z 555 MH^(+.)

Example 136α,9α-Difluoro-17α-(3,3-difluorocyclobutylcarbonyl)oxy-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester

Prepared from Intermediate 13 using methods similar to that describedfor Example 12. LCMS retention time 3.47 min, m/z 563 MH⁺

Example 146α,9α-Difluoro-11β-hydroxy-16α-methyl-17α-(1-methylcyclopentylcarbonyl)oxy-3-oxo-androsta-1,4-diene-17α-carbothioicacid S-fluoromethyl ester

Prepared from Intermediate 14 using methods similar to that describedfor Example 12. LCMS retention time 3.71 min, m/z 555 MH⁺

Example 156α,9α-Difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(3-oxocyclobutylcarbonyl)oxy-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester

Prepared from Intermediate 15 using methods similar to that describedfor Example 12. LCMS retention time 3.24 min, m/z 541 MH⁺

Preparation of Long Acting β₂-Adrenoreceptor Agonist

Example X3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-hexyl]oxy}butyl)benzenesulfonamideacetate i) Di(tert-butyl)2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethylimidodicarbonate

Cesium carbonate (70.4 g) was added to a stirred suspension of2-bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone, (Glaxo, DE3513885, 1985) (61.8 g) and di-t-butyl iminodicarboxylate (47.15 g) inacetonitrile (600 ml) under nitrogen. After vigorous stirring at 21° C.for 24 h the mixture was diluted with water (ca800 ml) and the productwas extracted with diethyl ether (1 liter, then 200 ml). The combinedorganic layers were washed with brine, dried (MgSO₄) and concentrated toca400 ml. The white crystals were collected by filtration, washed withdiethyl ether and dried to give the title compound (24.4 g) δ (CDCl₃)7.78 (1H, dd, J 8, 2 Hz), 7.65 (1H, brs), 6.87 (1H, d, J 8 Hz), 4.97(2H,s), 4.88(2H, s), 1.56(6H, s) and 1.48 (18H, s). Further concentration ofthe mother liquors gave additional product (13.8 g). A third crop (7.1g) was obtained by chromatographing the mother liquors on silica gel,evaporating the appropriate eluate and triturating with diethyl ether.

ii) tert-Butyl2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethylcarbamate

Trifluoroacetic acid (92 ml) was added to a stirred solution ofdi(tert-butyl)2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethylimidodicarbonate,(352.55 g) in dichloromethane (3.6 liters) at 21° C. and the reactionwas stirred for 1.5 h. Aqueous NaOH solution (1.75 liters) was added andafter 10 min the phases were separated. The organic layer was washedwith water, dried (MgSO₄) and evaporated to an oil. This was storedunder high vacuum overnight and then triturated with hexane:ether (3:1)to give the crude product (226.61 g). This was purified byrecrystallisation from diethyl ether to give the title compound (122.78g). Further product (61.5 g) was obtained from the mother liquors byevaporation and chromatography on a Biotage using 15% ethyl acetate inhexane. LCMS RT=3.37 min.

iii)tert-Butyl(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethylcarbamate

A 2M solution of borane-dimethyl sulphide in THF (28 ml) was addedslowly to a 1 M solution of(R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborolein toluene (56 ml) at 0° C. under nitrogen. A solution of tert-butyl2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethylcarbamate, (108.2 g)in THF (1.3 liters) was added slowly keeping the temperature below 5° C.followed by 2M solution of borane-dimethyl sulphide in THF (252 ml) over50 min. After 1 h, 2M HCl (170 ml) was added with cooling and themixture was partitioned between ethyl acetate and water. The organiclayer was washed with saturated NaHCO₃ solution and brine and dried(MgSO₄). The solution was concentrated and the product purified bychromatography on flash silica gel (800 g), eluting successively withhexane:ethyl acetate (4:1 then 3:1) to give the title compound (93.3 g),LCMS RT=3.31 min.

iv) (5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one

tert-Butyl(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethylcarbamate,(86.37 g) in DMF (600 ml) was added dropwise to a stirred suspension ofsodium hydride (60% oil dispersion, 11.9 g) in DMF (160 ml) with coolingsuch that the internal temperature remained at 0° C. under nitrogen. Themixture was stirred at 21° C. for 2 h. The mixture was recooled to 0° C.and 2M HCl (134 ml) was added. The mixture was diluted with water andthe product was extracted with ethyl acetate twice. The solution waswashed with brine twice, dried (MgSO₄) and evaporated to give the titlecompound (63.55 g) LCMS RT=2.66 min.

v) 6-Bromohexyl but-3-ynyl ether

3-Butyn-1-ol (42.4 ml) was stirred vigorously with 1,6-dibromohexane(260 ml) and tetrabutylammonium bisulphate (2.4 g) in 50% aqueous sodiumhydroxide solution (200 ml) under nitrogen for 3 days. Water (ca 700 ml)was added and the organic layer was separated. The aqueous layer wasextracted twice with dichloromethane (2×100 ml) and the combined organiclayers were washed with water, dried (MgSO₄) and concentrated. Theresidue in petroleum ether (bp 40–60°) was loaded onto a column ofsilica gel (1.5 kg) and the column was eluted with petroleum ether (bp40–60° C.), then 10% diethyl ether in petroleum ether (bp 40–60° C.) togive the title compound (103.3 g), 8 (CDCl₃) 3.56(2H, t, J 7 Hz),3.47(2H, t, J 7 Hz), 3.42(2H, t. J 7 Hz), 2.45(2H, m), 1.99(1H, t, J 2Hz),1.87(2H, m), 1.60(2H, m) and 1.50 to 1.33 (4H, m).

vi)(5R)-3-[6-(But-3-ynyloxy)hexyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one

(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (10g) in DMF (100 ml) was added dropwise to a stirred suspension of sodiumhydride (60% oil dispersion, 2.33 g) in DMF (50 ml) with stirring undernitrogen and maintaining the internal temperature at 0° C. Stirring wascontinued at 0–5° C. for 1 h. The mixture was recooled to 0° C. and asolution of 6-bromohexyl but-3-ynyl ether (14.7 g) in DMF (50 ml) wasadded over 1 min. The mixture was then stirred at 20–30° C. for 2 h. 2MHCl (9 ml) was added and the mixture was partitioned between water anddiethyl ether. The aqueous layer was extracted with more diethyl etherand the combined organic layers were washed twice with brine. Afterdrying (MgSO₄) the solution was concentrated and loaded onto a column ofsilica gel (600 g) set up in diethyl ether:petroleum ether (bp 40–60°C.) (1:2). The column was eluted successively with this mixture, then(1:1) and then diethyl ether to give the title compound (13.88 g) LCMSRT=3.45 min.

vii)3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]benzenesulfonamide

(5R)-3-[6-(But-3-ynyloxy)hexyl]5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one(1.79 g) was stirred with 3-iodobenzene sulphonamide (1.4 g) inacetonitrile:triethylamine (1:1, 42 ml) under nitrogen for 10 min.Cuprous iodide (0.083 g) and dichlorobis(triphenylphosphine)palladium(0.192 g) were added and the mixture was stirred for 17 h under nitrogenat 21° C. The mixture was evaporated to dryness and the residue waschromatographed on silica gel (250 g) in 30% ethyl acetate: petroleumether (bp 40–60°), then 50%, then 75% and finally ethyl acetate to givethe title compound (2.35 g), LCMS RT=3.44 min.

viii)3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]benzenesulfonamide

3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]benzenesulfonamide(2.35 g) was stirred with platinum oxide (0.3 g) in THF (30 ml) underhydrogen for 2 h. The catalyst was removed by filtration using a filteraid and the filter cake was leached with ethyl acetate. The combinedfiltrates were passed through silica gel (200 g) in ethyl acetate andthe eluate was evaporated to give the title compound (2.32 g), LCMSRT=3.49 min.

ix)3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide

3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]benzenesulfonamide(0.43 g) was stirred in THF (10 ml) while purging with a vigorous streamof nitrogen for 5 min. Potassium trimethylsilanoate (0.43 g) was addedand the mixture was stirred at 70° C. under nitrogen for 2.5 h. Themixture was partitioned between dichloromethane and pH 6.4 phosphatebuffer and the aqueous layer was extracted with more dichloromethane.The combined organic layers were washed with water, dried (MgSO₄) andconcentrated. The residue was purified on silica gel (60 g), elutingsuccessively with ethyl acetate:petroleum ether (bp 40–60° C.) (1:1),ethyl acetate, 10% then 20% methanol in ethyl acetate to give the titlecompound (0.286 g), LCMS RT=2.56 min.

x)3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-hexyl]oxy}butyl)benzenesulfonamideacetate

3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide(0.283 g) was stirred with acetic acid (8 ml) and water (4 ml) at 70°for 35 min before evaporating to dryness. The residue was re-evaporatedtwice with toluene to give the title compound (0.318 g) LCMS RT=2.34min, ES+ve 495 (MH)⁺.

Pharmacological Activity

Pharmacological activity was assessed in a functional in vitro assay ofglucocorticoid agonist activity which is generally predictive ofanti-inflammatory or anti-allergic activity in vivo.

The functional assay was based on that described by K. P. Ray et al.,Biochem J. (1997), 328, 707–715. A549 cells stably transfected with areporter gene containing the NF-κB responsive elements from the ELAMgene promoter coupled to sPAP (secreted alkaline phosphatase) weretreated with test compounds at appropriate doses for 1 hour at 37° C.The cells were then stimulated with tumour necrosis factor (TNF, 10ng/ml) for 16 hours, at which time the amount of alkaline phosphataseproduced is measured by a standard colourimetric assay. Dose responsecurves were constructed from which EC₅₀ values were estimated. In thistest the compounds of Examples 1 to 15 showed an EC₅₀ value of <2 nM.

Screen for Progesterone Receptor Activity

The human breast cancer cell line T47D has been reported to upregulatean endogenous alkaline phosphatase in response to progestins (Di Lorenzoet al., Cancer Research (1991) 51, 4470–4475. T47D cells were seededinto 96 well plates at a density of 1×10⁵ cells per well and grownovernight at 37° C. Steroids were dissolved in DMSO, added to the cells(final DMSO concentration 0.7%), and incubated for 24 hours at 37° C.The cells were then washed with PBS and lysed with RIPA buffer (1%IGEPAL, 0.5% Na deoxycholate, 0.1% SDS in phosphate buffered saline).Alkaline phosphatase activity was measured spectrophotometrically (405nm) using p-nitrophenylphosphate (1.5 mg/ml) as a substrate dissolved in1M diethanolamine, 0.28M NaCl, 0.5 mM MgCl₂. Dose response curves wereconstructed from which EC₅₀ values were estimated.

Examples 5 and 11 were tested for progesterone activity in accordancewith the above screen and the selectivity was determined by dividing theED₅₀ at the progesterone receptor by the ED₅₀ at the glucocorticoidreceptor. The selectivity of Example 5 was 353 (compare fluticasonepropionate: selectivity=57) and of Example 11 was 1230 (comparefluticasone propionate: selectivity=107).

Throughout the specification and the claims which follow, unless thecontext requires otherwise, the word ‘comprise’, and variations such as‘comprises’ and ‘comprising’, will be understood to imply the inclusionof a stated integer or step or group of integers but not to theexclusion of any other integer or step or group of integers or steps.The patents and patent applications described in this application areherein incorporated by reference.

1. A compound of formula (I)

wherein R₁ represents C₁₋₆ alkyl or C₁₋₆ haloalkyl; R₂ represents C₃₋₈cycloalkyl or C₃₋₈ cycloalkenyl either of which may optionally besubstituted by one or more groups selected from oxo, methyl, methyleneand halogen; R₃ represents hydrogen, methyl (which may be in either theα or β configuration) or methylene; R₄ and R₅ are the same or differentand each represents hydrogen or halogen; and

represents a single or a double bond; or a solvate thereof.
 2. Acompound according to claim 1 in which R₂ represents C₃₋₈ cycloalkyl orC₃₋₈ cycloallcenyl either of which may optionally be substituted by oneor more groups selected from methyl, metbylene and halogen.
 3. Acompound according to claim 1 in which R₂ represents C₃₋₆ cycloalkyloptionally substituted by one or more methyl and/or chlorine groups. 4.A compound according to claim 1 in which R₁ represents fluoromethyl,chloromethyl, bromomethyl or 2′-fluoroethyl.
 5. A compound according toclaim 4 in which R₁ represents fluoromethyl.
 6. A compound according toclaim 1 in which R₃ is methyl.
 7. A compound according to claim 1 inwhich R₄ and R₅ are the same or different and each represents hydrogen,fluorine or chlorine.
 8. A compound according to claim 7 in which R₄ andR₅ are the same or different and each represents hydrogen or fluorine.9. A compound according to claim 8 in which both R₄ and R₅ are fluorine.10. A compound according to claim 1 in which

represents a double bond.
 11. A compound according to claim 1 which is:17α-(Cyclobutylcarbonyl)oxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester;17α-(Cyclopentylcarbonyl)oxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester;17α-(Cyclohexylcarbonyl)oxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester;17α-(Cyclopropylcarbonyl)oxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester; or a solvate of any one thereof.
 12. Acompound according to claim 1 which is:6α,9α-Difluoro-11β-hydroxy-16α-methyl-17α-(1-methycyclopropylcarbonyl)oxy-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester;6α,9α-Difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(2,2,3,3-tetramethycyclopropylcarbonyl)oxy-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester;17α-(2,2-Dichloro-1-methycyclopropylcarbonyl)oxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester;17α-(2,2-Dichlorocylopropylcarbonyl)oxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester;6α,9α-Difluoro-11β-hydroxy-16α-methyl-17α-(3-methylenecyclobutylcarbonyl)oxy-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester;6α,9α-Difluoro-11β-hydroxy-16α-methyl-1,7α-(2-methylcyclopropylcarbonyl)oxy-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester; or a solvate of any one thereof.
 13. Acompound according to claim 1 which is:6α,9α-Difluoro-11β-hydroxy-16α-methyl-17α-(1-methylcyclobutylcarbonyl)oxy-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester;or a solvate thereof.
 14. A compound according to claim 1 which is:6α,9α-Difluoro-17α-(3,3-dimethylcyclobutylcarbonyl)oxy-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester;6α,9α-Difluoro-17α-(3,3-difluorocyclobutylcarbonyl)oxy-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester;6α,9α-Difluoro-11β-hydroxy-16α-methyl-17α-(1-methylcyclopentylcarbonyl)oxy-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester;6α,9α-Difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(3-oxocyclobutylcarbonyl)oxy-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester; or a solvate of any one thereof.
 15. Acompound:6α,9α-Difluoro-11β-hydroxy-16α-methyl-17α-(1-methycyclopropylcarbonyl)oxy-3-oxo-androsta- 1 ,4-diene- 17β-carbothioic acid S-fluoromethylester or a physiologically acceptable solvate thereof.
 16. Apharmaceutical composition comprising a compound of formula (I) asdefined in claim 1 or a physiologically acceptable solvate thereof inadmixture with one or more physiologically acceptable diluents orcarriers.
 17. A pharmaceutical aerosol formulation comprising a compoundof formula (I) as defined in claim 1 or a physiologically acceptablesolvate thereof, and a fluorocarbon or hydrogen-containing chlorofluorocarbon as propellant, optionally in combination with a surfactant and ora cosolvent.
 18. A pharmaceutical composition according to claim 16which further comprises another therapeutically active agent.
 19. Apharmaceutical composition according to claim 18 in which said anothertherapeutically active agent is a β₂-adrenoreceptor agonist.
 20. Apharmaceutical composition according to claim 19 in which saidβ₂-adrenoreceptor agonist is a compound of formula (X):

or a salt or solvate thereof, wherein: m is an integer of from 2 to 8; nis an integer of from 3 to 11, with the proviso that m+n is 5 to 19, R¹¹is —XSO₂NR¹⁶R¹⁷ wherein X is —(CH₂)_(p)— or C₂₋₆ alkenylene; R¹⁶ and R¹⁷are independently selected from hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl,C(O)NR¹⁸R¹⁹, phenyl, and phenyl (C₁₋₄alkyl)-, or R¹⁶ and R¹⁷, togetherwith the nitrogen to which they are bonded, form a 5-, 6-, or 7-memberednitrogen containing ring, and R¹⁶ and R¹⁷ are each optionallysubstituted by one or two groups selected from halo, C₁₋₆alkyl,C₁₋₆haloalkyl, C₁₋₆alkoxy, hydroxy-substituted C₁₋₆alkoxy, —CO₂R¹⁸,—SO₂NR¹⁸R¹⁹, —CONR¹⁸R¹⁹, —NR¹⁸C(O)R¹⁹, or a 5-, 6- or 7-memberedheterocylic ring; R¹⁸ and R¹⁹ are independently selected from hydrogen,C₁₋₆alkyl, C₃₋₆cycloalkyl, phenyl, and phenyl (C₁₋₄alkyl)-; and p is aninteger of from 0 to 6; R¹² and R¹³ are independently selected fromhydrogen, C₁₋₆alkyl, C₁₋₆alkoxy, halo, phenyl, and C₁₋₆haloalkyl; andR¹⁴ and R¹⁵ are independently selected from hydrogen and C₁₋₄alkyl withthe proviso that the total number of carbon atoms in R¹⁴ and R¹⁵ is notmore than
 4. 21. A pharmaceutical composition according to claim 19 inwhich the compound of formula (X) is3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-hexyl]oxy}butyl)benzenesulfonamideor a salt or solvate thereof.
 22. A pharmaceutical composition accordingto claim 18 in which said another therapeutically active agent is anantihistamine.
 23. A pharmaceutical composition according to claim 22 inwhich said antihistamine is methapyrilene or loratadine.
 24. Apharmaceutical composition according to claim 22 in which the compoundof formula (I) is6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-(1-methycyclopropylcarbonyl)oxy-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester.
 25. A pharmaceutical composition according toclaim 23 in which the compound of formula (I) is6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-(1-methycyclopropylcarbonyl)oxy-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester.
 26. A pharmaceutical composition according toclaim 16 wherein the composition is a aerosol formulation administeredto the nose by a pump.
 27. A pharmaceutical composition according toclaim 16 wherein the composition is an aqueous aerosol formulation. 28.A pharmaceutical composition according to claim 27 wherein theformulation is non-pressurised and adapted to be administered topicallyto the nasal cavity.
 29. A pharmaceutical composition according to claim28 further comprising a buffering agent and/or a tonicity modifyingagent.
 30. The pharmaceutical composition according to claim 16 whereinthe pharmaceutical composition is in an aqueous formulation and isadministered to the nose by nebulisation.
 31. A pharmaceuticalcomposition comprising a compound as defined in claim 15 in admixturewith one or more physiologically acceptable diluents and/or carriers.32. A pharmaceutical composition according to claim 31 wherein thecomposition is an aerosol formulation.
 33. A pharmaceutical compositionaccording to claim 32 wherein the composition is an aqueous aerosolformulation.
 34. A pharmaceutical composition according to claim 33wherein the formulation is non-pressurised and adapted to beadministered topically to the nasal cavity.
 35. A pharmaceuticalcomposition according to claim 33 further comprising a buffering agentand/or a tonicity modifying agent.
 36. A method of treatment of at leastone inflammatory and/or allergic condition comprising delivery to apatient a compound of formula (I) as defined claim 1 or aphysiologically acceptable solvate thereof.
 37. A method for thetreatment of a human or animal subject with an anti-inflammatory and/orallergic condition, which method comprises administering to said humanor animal subject an effective amount of a compound of formula (I) asdefined in claim 1 or a physiologically acceptable solvate thereof. 38.A method of treatment of at least one inflammatory and/or allergiccondition comprising delivery to a patient a compound of claim
 15. 39.The method of treatment of claim 38 wherein the pharmaceuticalcomposition is an aqueous formulation and is administered to the nose.40. The method of treatment of claim 39 wherein said at least oneinflammatory and/or allergic condition is rhinitis.
 41. A method ofmaking a veterinary or human medicine comprising admixing a compound offormula (I) as defined in claim 1 or a physiologically acceptablesolvate thereof in a pharmaceutically acceptable dosage form.
 42. Amethod of making a veterinary or human medicine comprising admixing acompound of claim 15 in a pharmaceutically acceptable dosage form.
 43. Aprocess for preparing a compound of formula (I) according to claim 1which comprises alkylation of a compound of formula (II)

wherein R², R³, R⁴, R⁵ and

are as defined in claim
 1. 44. A process according to claim 28 whereinalkylation is performed by reacting the compound of formula (II) with anappropriate alkyl or haloalkyl halide.
 45. A compound of formula (II)

wherein R², R³, R⁴, R⁵ and

are as defined in claim 1.